Intramolecular [3 + 2] annulation of olefin-tethered cyclopropylamines

Article abstract of DOI:10.1021/jo9817671

Starting from readily available olefin-tethered tertiary aminocyclopropanes, we have developed a convenient [3 + 2] annulation reaction by means of one-electron oxidation which can be induced photochemically or chemically, followed by two sequential 5-exo radical cyclizations. The rate constants for the competing 1,5-hydrogen transfer in the β-immonium carbon radical intermediate have been estimated to fall between 1000 (6-exo) and 100 (7-exo and/or 8-endo) s^-1 at room temperature.

Full text of DOI:10.1021/jo9817671

8510
J . Org. Chem. 1998, 63, 8510-8514
In tr a m olecu la r [3 + 2] An n u la tion of Olefin -Teth er ed
Cyclop r op yla m in es
J ae Du Ha, J inhwa Lee, Silas C. Blackstock, and J in Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, Alabama 35487
Received August 31, 1998
Starting from readily available olefin-tethered tertiary aminocyclopropanes, we have developed a
convenient [3 + 2] annulation reaction by means of one-electron oxidation which can be induced
photochemically or chemically, followed by two sequential 5-exo radical cyclizations. The rate
constants for the competing 1,5-hydrogen transfer in the â-immonium carbon radical intermediate
have been estimated to fall between 1000 (6-exo) and 100 (7-exo and/or 8-endo) s-1 at room
temperature.
Sch em e 1
Tertiary aminocyclopropanes 1 can be prepared in good
yields by the Simmons-Smith cyclopropanation of enam-
ines or, more conveniently, by Ti(II)-mediated coupling
of terminal olefins and N,N-dialkylcarboxamides.1-5 They
resist ring cleavage by acids, bases, or electrophiles.6 We
recently developed a convenient method for facile ring
opening of these cyclopropylamines by photosensitized
oxidation (Scheme 1).7 The cyclopropylamine cation
radicals 1•+ undergo facile ring opening, followed by 1,5-
hydrogen shift(s) of the resulting â-immonium carbon
radicals 2, to afford the ring-opened ketones 5 upon
hydrolysis. Analogous ring opening of the cyclopropyl-
amine radical cations has been implicated as the mode
of inactivation by cyclopropylamines of cytochrome P-450
and monoamine oxidase.8 In light of the synthetic
potential and biological significance of cyclopropylamine
cation radicals, we decided to assess the relative rates of
1,5-hydrogen transfer (i.e., 2a f 3a ) of the â-immonium
carbon radical intermediate by employing competitive 5-,
6-, and 7-exo cyclization (e.g., 2a f 6) to the tethered
olefin (eq 1).9,10 Herein we report a new, intramolecular
(1) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413.
(2) Lee, J .; Cha, J . K. J . Org. Chem. 1997, 62, 1584.
[3 + 2] annulation of olefin-tethered cyclopropylamines
(3) This new synthetic method for electron-donor substituted cyclo-
propanes, in turn, evolved from the original Kulinkovich procedure:
(a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya,
T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O. G.; Sviridov,
S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh. Org.
Khim. 1991, 27, 294. (c) Kulinkovich, O. G.; Sorokin, V. L.; Kel’in, A.
V. Zh. Org. Khim. 1993, 29, 66.
(4) (a) Lee, J .; Kang, C. H.; Kim, H.; Cha, J . K. J . Am. Chem. Soc.
1996, 118, 291. (b) Lee, J .; Kim, H.; Cha, J . K. J . Am. Chem. Soc. 1996,
118, 4198. (c) Lee, J .; Kim, Y. G.; Bae, J .; Cha, J . K. J . Org. Chem.
1996, 61, 4878. (d) Cho, S. Y.; Lee, J .; Lammi, R. K.; Cha, J . K. J . Org.
Chem. 1997, 62, 8235. See also: (e) Lee, J .; Kim, H.; Cha, J . K. J . Am.
Chem. Soc. 1995, 117, 9919. (f) Lee, J .; Cha, J . K. Tetrahedron Lett.
1996, 37, 3663. (g) U, J . S.; Lee, J .; Cha, J . K. Tetrahedron Lett. 1997,
38, 5233. (h) Lee, J .; Ha, J . D.; Cha, J . K. J . Am. Chem. Soc. 1997,
119, 8127.
(5) See also: (a) Corey, E. J .; Rao, S. A.; Noe, M. C. J . Am. Chem.
Soc. 1994, 116, 9345. (b) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995,
36, 6079. (c) Kasatkin, A.; Kobayashi, K.; Okamoto, S.; Sato, F.
Tetrahedron Lett. 1996, 37, 1849 and references therein.
(6) Kuehne, M. E.; King, J . C. J . Org. Chem. 1973, 38, 304.
(7) Lee, J .; U, J . S.; Blackstock, S. C.; Cha, J . K. J . Am. Chem. Soc.
1997, 119, 10241.
(8) See, inter alia: (a) Guengerich, F. P.; Macdonald, T. L. Adv.
Electron Transfer Chem. 1993, 3, 191. (b) Hanzlik, R. P.; Tullman, R.
H. J . Am. Chem. Soc. 1982, 104, 2048. (c) Silverman, R. B. J . Biol.
Chem. 1983, 258, 14766. See also: (d) Pirrung, M. C. J . Am. Chem.
Soc. 1983, 105, 7207.
by photosensitized and chemical oxidation.11-13
(9) For recent investigations on kinetics of other aminium radical
reactions, see: (a) Goez, M.; Satorius, I. J . Am. Chem. Soc. 1993, 115,
11123. (b) Horner, J . H.; Martinez, F. N.; Musa, O. M.; Newcomb, M.;
Shahin, H. E. J . Am. Chem. Soc. 1995, 117, 11124. (c) Musa, O. M.;
Horner, J . H.; Shahin, H.; Newcomb, M. J . Am. Chem. Soc. 1996, 118,
3862. Cf.: (d) Maeda, Y.; Ingold, K. U. J . Am. Chem. Soc. 1980, 102,
328.
(10) For recent examples of intramolecular hydrogen atom transfer,
see inter alia: (a) Beckwith, A. L. J .; Ingold, K. U. In Rearrangements
in the Ground and Excited States; de Mayo, P., Ed.; Academic: New
York, 1980; Vol. 1, p 161. (b) Baldwin, J . E.; Adlington, R. M.;
Robertson, J . Tetrahedron 1989, 45, 909. (c) Snieckus, V.; Cuevas, J .-
C.; Sloan, C. P.; Liu, H.; Curran, D. P. J . Am. Chem. Soc. 1990, 112,
896. (d) White, J . D.; J effrey, S. C. Synlett 1995, 831.
(11) In a previous communication (footnote 17 of ref 7), we had
disclosed that the ring-opened, â-immonium carbon radical can be
trapped effectively by a tethered olefin by means of 5-exo cyclization,
affording efficient bicyclic annulation.
(12) A recent report on the related CAN-mediated cyclization
prompted us to report our own results: Takemoto, Y.; Yamagata, S.;
Furuse, S.-i.; Hayase, H.; Echigo, T.; Iwata, C. J . Chem. Soc., Chem.
Commun. 1998, 651.
(13) Cyclopropyl sulfides bearing a benzylidene moiety were shown
to undergo similiar cyclization: Takemoto, Y.; Furuse, S.-i.; Koike, H.;
Ohra, T.; Iwata, C.; Ohishi, H. Tetrahedron Lett. 1995, 36, 4085.
10.1021/jo9817671 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/16/1998

Annulation of Olefin-Tethered Cyclopropylamines
J . Org. Chem., Vol. 63, No. 23, 1998 8511
Ta ble 1.
The starting materials 1 were readily prepared in a
single step by Ti(II)-mediated coupling of the correspond-
ing dienes.2 The trans-1,2-dialkyl (major) isomers were
used for photooxidation experiments (Table 1). In a
typical experiment, a deaerated solution of cyclopropy-
lamine 7a in 10:1 MeCN-H2O containing 1.5 equiv of
1,4-dicyanobenzene (DCB) was irradiated for 1 h; the
bicyclic amine 8a was isolated as a single diastereomer
in 91% yield (based on 66% conversion) (entry 1, Table
1). The expected â-immonium carbon radical 2a prefer-
entially undergoes 5-exo cyclization over the competing
1,5-hydrogen transfer to afford a new radical 6. A second
intramolecular cyclization, followed by reduction with
DCB•-, then affords the annulation product. On the basis
of steric considerations (see 6A), its stereochemistry is
tentatively assigned as 8a . The observation that replace-
ment of the propyl group by the bulkier cyclopentyl unit
(see 13A) resulted in the stereorandom (1:1) production
of two diastereomers 14 (entry 6) supports this stereo-
chemical assignment (compare also entry 5 vs entries 8
and 9). Both trans- and cis-1,2-dialkyl diastereomers, 7a
and 10, gave the identical photooxidation product 8a
(entry 4). Photooxidation of the homologue 7b also
furnished the amino-substituted bicyclo[4.3.0]nonane 8b
in 47% (unoptimized) yield (based on 75% conversion).
On the other hand, no cyclization product 8c, but only
the ketone 9c, was obtained (60% yield) from the homo-
logue 7c. The rate constants for 1,5-hydrogen transfer
in these systems are estimated to fall between 1000 (6-
exo) and 100 (7-exo and/or 8-endo) s-1 at room temper-
ature.
isomer in 50% yield (based on 60% conversion).14 Al-
though the yield remains to be optimized, it is noteworthy
that the two-step sequence involving cyclopropanation of
(14) Whereas the stereochemistry has not been assigned yet, it is
likely that 16 has the piperidine ring in the â configuration (with the
R configuration of the cyclopentyl group).
The fused tricyclic product 16 was obtained as a single

8512 J . Org. Chem., Vol. 63, No. 23, 1998
Ha et al.
Ta ble 2. P h otosen sitized Oxid a tion of
Cyclop r op yla m in es 7a a n d 13 in Sever a l Solven t System s
Table 1) could 10:1 CH3CN-MeOH be utilized as the
solvent to achieve comparable yields. It is interesting
to note that the annulation reaction proceeds faster in
10:1 CH3CN-H2O than in CH3CN-MeOH.
The undesired oxidative decomposition likely involves
R-CH deprotonation, a well-documented reaction, of the
aminium radicals17 and appears to be more pronounced
for small alkyl substituents (such as methyl) at the amine
group. For example, the nitrile 23 was obtained as the
only isolable product (as a single diastereomer) in 20%
yield from photooxidation of cyclopropylamine 21 (eq 2).
Next, R-CH deprotonation of the aminium radicals was
explored concurrently with the oxidation of the resulting
neutral R-amino radicals of type 27 (or 24) to generate
immonium ions 28, which should be inert to further
oxidation (eq 3). Treatment of 7a with ceric ammonium
nitrate (CAN) (5 equiv of CAN, 5 equiv of NaHCO3, in
5:1 MeOH-CH2Cl2) afforded the secondary amine 25 in
61% yield, along with amide 26 (15%), ketone 9a (5%),
and unreacted 7a (10%).18 The results of the use of other
solvents are tabulated in Table 3. Mechanistically, the
CAN-mediated [3 + 2] annulation reaction parallels the
photooxidative process, but the main difference emerges
only after the formation of the initial annulation prod-
ucts. Under CAN oxidation, the original annulation
products undergo further oxidation to result in dealky-
lation, whereas such a pathway is precluded in the
photosensitized oxidation by the presence of DCB•-. The
[3 + 2] annulation reaction is anticipated to be general
and tolerant of a wide range of substitution patterns: it
is by no means limited to N-benzylamino cyclopropanes.19
a readily available diene and subsequent photooxida-
tion provides convenient, easy access to the structurally
complex triquinane ring system.
As can be seen from the examples in Table 1, a short-
coming of this novel [3 + 2] annulation reaction centers
around low conversion. The crux of the problem is posed
by the fact that the tertiary amine functionality of the
annulation products is also susceptible to photooxidation;
in fact, the amine products are anticipated to possess
lower ionization and oxidation potentials than the start-
ing materials because of the greater s character of the
cyclopropyl group (compared to an sp3 alkyl).15 Indeed,
prolonged irradiation resulted in poor yields due to
further oxidative degradation of the desired product. In
attempts to protect the tertiary amine products from such
degradation by means of selective protonation, use of a
(pH 7 or 9 phosphate) buffer and aqueous NH4Cl solution,
in addition to 10:1 CH3CN-MeOH,16a was investigated
(Table 2). Unfortunately, none of the variations afforded
the desired selective shield to the products; the best
results were obtained by use of 10:1 CH3CN-H2O.16b
Only when sterically demanding groups are present at
and near the amine (i.e., entries 7-9 vs entries 1-6,
(17) Cf.: (a) Nelsen, S. F. In Free Radicals; Kochi, J . K., Ed.; Wiley:
New York, 1973; Vol. 2, Chapter 21. (b) Chow, Y. L.; Danen, W. C.;
Nelsen, S. F.; Rosenblatt, D. H. Chem. Rev. 1978, 78, 243. (c) Stella,
L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337. (d) Newcomb, M.; Deeb,
T. M. J . Am. Chem. Soc. 1987, 109, 3163. (e) Zhang, X.; Yeh, S.-R.;
Hong, S.; Freccero, M.; Albini, A.; Falvey, D. E.; Mariano, P. S. J . Am.
Chem. Soc. 1994, 116, 4211 and references therein.
(18) The formamide formation is presumed to arise from oxidation
of the enamine intermediate 29. The detailed mechanism must await
further study. Cf.: (a) J erussi, R. A. J . Org. Chem. 1969, 34, 3648. (b)
Blau, K.; Voerckel, V. J . Prakt. Chem. 1989, 331, 285.
(19) Iwata and co-workers have recently reported facile debenzyla-
tion in similar CAN-mediated annulation reactions of N-benzyl cyclo-
propylamines.12 On the basis of our present findings, we believe their
proposed timing of debenzylation is incorrect; the correct debenzylation
mechanism involves the identical sequence as described for 8a f 27
f 28 f 25.
(15) For example, cyclopropyl(dimethyl)amine was found to be less
+
+
basic (pKBH ) 7.7) than cyclohexyl(dimethyl)amine (pKBH ) 9.2):
Roberts, J . D.; Chambers, V. C. J . Am. Chem. Soc. 1951, 73, 5030.
(16) (a) This solvent system was originally and successfully em-
ployed for the generation of the ring-opened ketones by photosensitized
oxidation of tertiary aminocyclopropanes (ref 7). (b) While the reason
for the beneficial effect of water is presently unclear, it is tempting to
speculate that it might be in part due to H-bonding between water
and the tertiary amine.

Annulation of Olefin-Tethered Cyclopropylamines
J . Org. Chem., Vol. 63, No. 23, 1998 8513
Ta ble 3. CAN Oxid a tion of Cyclop r op yla m in e 7a Un d er
Sever a l Con d ition s
sion photochemical reactor (equipped with a medium-pressure
mercury lamp) and deaerated with nitrogen. The reaction
mixture was irradiated at room temperature for 1 h under a
nitrogen atmosphere. After the lamp was turned off, the
resulting mixture was extracted with EtOAc (2 × 20 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (5:1
hexane-EtOAc) to afford the bicyclic annulation product 8a
(17 mg, 60%), along with 10 mg (34%) of the recovered
cyclopropylamine (as a ∼4:1 mixture of cis- and trans-1,2-
dialkyl isomers, 7a and 10).
1
8a : H NMR (360 MHz, CDCl3) δ 0.88 (t, J ) 7.2 Hz, 3 H),
0.89 (t, J ) 6.9 Hz, 3 H), 0.96 (t, J ) 7.0 Hz, 6 H), 1.15-1.65
(m, 20 H), 1.74 (dd, J ) 8.0, 12.4 Hz, 1 H), 1.94 (m, 1 H), 2.25
(m, 1 H), 2.59 (q, J ) 7.0 Hz, 4 H); 13C NMR (90 MHz, CDCl3)
δ 14.1, 15.2, 17.0, 17.5, 22.7, 25.7, 28.9, 32.1, 32.7, 33.2, 34.9,
35.0, 39.4, 41.3, 43.3, 49.1, 52.6, 71.2; MS m/z 293 (M+, 2),
222 (49), 191 (58), 149 (100), 121 (76); HRMS (M+) 293.3082
calcd for C20H39N, found 293.3078.
8b: 1H NMR (360 MHz, CDCl3) δ 0.89 (t, J ) 7.2 Hz, 6 H),
1.01 (t, J ) 7.1 Hz, 6 H), 1.10-1.57 (m, 19 H), 1.58 (m, 1 H),
1.64-1.81 (m, 4 H), 2.02 (m, 1 H), 2.44 (dq, J ) 14.0, 7.1 Hz,
2 H), 2.51 (dq, J ) 14.0, 7.1 Hz, 2 H); 13C NMR (90 MHz,
CDCl3) δ 14.1, 15.1, 17.1, 17.9, 22.6, 26.3, 26.6, 29.7, 29.9, 31.4,
31.7, 32.3, 32.9, 38.7, 43.9, 44.0, 44.5, 50.8, 53.1, 69.6; MS m/z
307 (M+, 1), 216 (53), 187 (78), 163 (76), 121 (100); HRMS (M+)
307.3239 calcd for C21H41N, found 307.3232.
9c: IR (CH2Cl2) 1709 cm-1 1H NMR (360 MHz, CDCl3) δ
;
0.88 (t, J ) 7.1 Hz, 3 H), 0.91 (t, J ) 7.5 Hz, 3 H), 1.28 (m, 14
H), 1.58 (m, 4 H), 2.00 (m, 4 H), 2.36 (t, J ) 7.3 Hz, 2 H), 2.37
(t, J ) 7.4 Hz, 2 H), 5.35 (m, 2 H); 13C NMR (90 MHz, CDCl3)
δ 13.8, 14.1, 17.3, 22.6, 23.8, 27.2, 29.1, 29.2, 29.3, 29.4, 29.7,
31.5, 32.5, 42.8, 44.7, 129.8, 129.9, 211.5; MS m/z 266 (M+,
22), 223 (79), 178 (49), 153 (86), 125 (100); HRMS (M+)
266.2609 calcd for C18H34O, found 266.2599.
*The ketone 9a was admixed with inseparable, unidentified
byproducts.
1
12: H NMR (360 MHz, CDCl3) δ 0.94 (t, J ) 7.2 Hz, 3 H),
1.04 (t, J ) 7.1 Hz, 6 H), 1.14-1.45 (m, 12 H), 1.65 (m, 1 H),
1.79 (m, 2 H), 2.05 (m, 1 H), 2.25 (m, 1 H), 2.72 (q, J ) 7.1 Hz,
4 H), 7.21 (m, 5 H); 13C NMR (90 MHz, CDCl3) δ 15.2, 17.1,
17.5, 25.4, 33.2, 33.8, 34.8, 38.1, 39.0, 40.9, 43.2, 48.2, 54.7,
71.3, 125.4, 128.1, 129.0, 142.6.
14 (on e d ia ster eom er ): 1H NMR (360 MHz, CDCl3) δ 0.89
(t, J ) 6.7 Hz, 3 H), 1.01 (t, J ) 7.0 Hz, 6 H), 1.15-1.69 (m, 24
H), 1.94 (dd, J ) 8.4, 14.1 Hz, 1 H), 2.22 (m, 1 H), 2.34 (m, 1
H), 2.47 (m, 1 H), 2.68 (dq, J ) 14.0, 7.0 Hz, 2 H), 2.77 (dq, J
) 14.0, 7.0 Hz, 2 H); 13C NMR (90 MHz, CDCl3) δ 14.2, 17.1,
22.7, 25.3, 25.7, 26.4, 29.2, 29.3, 30.0, 31.9, 33.0, 34.1, 34.3,
39.0, 41.3, 44.3, 45.1, 50.8, 55.9, 75.7; MS m/z 319 (M+, 1),
246 (17), 222 (20), 175 (100), 133 (37); HRMS (M+) 319.3239
calcd for C22H41N, found 319.3220.
14 (th e oth er d ia ster eom er ): 1H NMR (360 MHz, CDCl3)
δ 0.89 (t, J ) 6.7 Hz, 3 H), 0.96 (t, J ) 7.0 Hz, 6 H), 1.15-1.70
(m, 24 H), 1.91 (dd, J ) 8.8, 13.3 Hz, 1 H), 1.99 (m, 1 H), 2.11
(m, 1 H), 2.30 (m, 1 H), 2.55 (ddq, J ) 13.5, 13.5, 7.0 Hz, 4 H);
13C NMR (90 MHz, CDCl3) δ 14.2, 17.4, 22.8, 24.9, 25.8, 26.1,
27.5, 29.1, 30.4, 32.8, 33.2, 34.5, 35.7, 39.4, 41.1, 43.7, 44.7,
50.4, 54.4, 74.2.
In summary, starting from readily available olefin-
tethered cyclopropylamines, we have developed a conve-
nient [3 + 2] annulation reaction by means of one-
electron oxidation which can be induced photochemically
or chemically, followed by two sequential 5-exo radical
cyclizations. The rate constants for the competing 1,5-
hydrogen transfer in the â-immonium carbon radical
intermediate have been estimated to fall between 1000
(6-exo) and 100 (7-exo and/or 8-endo) s-1 at room tem-
perature. Further optimization and comparison studies
of the photochemical and chemical [3 + 2] annulation
methods, along with synthetic applications, will be
reported in due course.
16: 1H NMR (360 MHz, CDCl3) δ 1.25-1.83 (m, 27 H), 1.91-
2.02 (m, 2 H), 2.09 (m, 1 H), 2.30 (m, 1 H), 2.68 (m, 4 H); 13C
NMR (90 MHz, CDCl3) δ 25.2, 25.6, 26.0, 26.7, 27.9, 28.4, 29.4,
29.8, 32.3, 40.2, 42.0, 42.3, 46.1, 48.7, 50.0, 60.4, 73.3; MS m/z
301 (M+, 2), 232 (100), 216 (58), 187 (67), 173 (64), 147 (42),
119 (46); HRMS (M+) 301.2769 calcd for C21H35N, found
301.2762.
18 (on e d ia ster eom er ): 1H NMR (360 MHz, CDCl3) δ 0.89
(t, J ) 6.5 Hz, 3 H), 1.06 (dd, J ) 10.2, 13.7 Hz, 1 H), 1.11-
1.63 (m, 30 H), 1.86 (dd, J ) 7.7, 13.7 Hz, 1 H), 2.20 (m, 1 H),
2.35 (m, 1 H), 2.63 (br s, 4 H); 13C NMR (90 MHz, CDCl3) δ
14.2, 22.7, 25.2, 25.7, 26.0, 28.0, 28.9, 29.1, 29.7, 29.8, 32.0,
32.9, 33.6, 33.8, 36.9, 40.4, 43.1, 50.0, 50.4, 55.8, 73.8; MS m/z
331 (M+, 3), 262 (59), 217 (18), 175 (100), 133 (30); HRMS (M+)
331.3239 calcd for C23H41N, found 331.3231.
Exp er im en ta l Section
A Rep r esen ta tive P r oced u r e for P h otosen sitized Oxi-
dation of Olefin -Teth er ed N,N-Dialkylcyclopr opylam in es.
A mixture of the tertiary aminocyclopropane 7a (29 mg, 0.1
mmol) and 1,4-dicyanobenzene (19 mg, 0.15 mmol) in 10:1
CH3CN-H2O (33 mL) was placed in a Hanovia 450-W immer-
20 (on e d ia ster eom er ): 1H NMR (360 MHz, CDCl3) δ 0.83
(d, J ) 6.4 Hz, 3 H), 0.91 (d, J ) 6.4 Hz, 3 H), 1.08 (dd, J )
10.3, 13.7 Hz, 1 H), 1.16-1.62 (m, 23 H), 1.64 (m, 1 H), 1.86

8514 J . Org. Chem., Vol. 63, No. 23, 1998
Ha et al.
1
(dd, J ) 7.8, 13.7 Hz, 1 H), 2.18 (m, 1 H), 2.25 (m, 2 H), 2.63
(br s, 4 H); 13C NMR (90 MHz, CDCl3) δ 22.2, 24.7, 25.3, 25.7,
25.9, 26.0, 26.2, 28.0, 28.7, 29.8, 33.4, 33.7, 37.0, 40.6, 41.7,
43.0, 50.0, 50.7, 52.6, 74.0; MS m/z 317 (M+, 4), 274 (30), 248
(87), 176 (100), 133 (50); HRMS (M+) 317.3082 calcd for
25: H NMR (360 MHz, CDCl3) δ 0.88 (t, J ) 6.7 Hz, 3 H),
0.94 (t, J ) 6.6 Hz, 3 H), 1.19-1.70 (m, 19 H), 1.35 (t, J ) 7.2
Hz, 3 H), 1.88 (m, 1 H), 2.06 (m, 1 H), 2.17 (dd, J ) 7.9, 12.6
Hz, 1 H), 2.39 (m, 1 H), 2.93 (m, 1 H), 3.04 (m, 1 H); 13C NMR
(90 MHz, CDCl3) δ 12.2, 14.0, 14.7, 16.7, 22.7, 25.1, 28.2, 30.8,
32.4, 32.7, 32.9, 34.5, 38.5, 39.8, 40.3, 49.0, 52.9, 70.6.
C
22H39N, found 317.3099.
23: 1H NMR (360 MHz, CDCl3) δ 0.89 (d, J ) 6.4 Hz, 3 H),
26: IR (CH2Cl2) 2934, 1659 cm-1; 1H NMR (360 MHz, CDCl3)
δ 0.89 (t, J ) 6.7 Hz, 3 H), 0.92 (t, J ) 7.3 Hz, 3 H), 1.11 (t, J
) 7.0 Hz, 3 H), 1.15-1.72 (m, 20 H), 2.03 (m, 1 H), 2.08 (dd,
J ) 7.7, 12.3 Hz, 1 H), 2.41 (m, 1 H), 3.12 (dq, J ) 14.0, 7.0
Hz, 1 H), 3.52 (dq, J ) 14.0, 7.0 Hz, 1 H), 8.21 (s, 1 H); 13C
NMR (90 MHz, CDCl3) δ 14.0, 14.4, 14.6, 16.3, 22.6, 25.3, 28.4,
30.3, 32.3, 32.4, 32.6, 34.4, 35.6, 39.3, 41.1, 47.7, 54.2, 70.4,
162.5.
0.92 (d, J ) 6.4 Hz, 3 H), 1.01 (s, 3 H), 1.17 (m, 2 H), 1.37 (m,
1 H), 1.44 (m, 2 H), 1.50-1.77 (m, 6 H), 1.72 (dd, J ) 10.3,
13.7 Hz, 1 H), 1.97 (m, 1 H), 2.36 (m, 1 H), 2.41 (s, 3 H), 3.50
(d, A of ABq, J ) 17.5 Hz, 1 H), 3.66 (d, B of ABq, J ) 17.5
Hz, 1 H); 13C NMR (90 MHz, CDCl3) δ 19.5, 21.6, 24.7, 25.6,
25.7, 33.1, 33.9, 35.8, 38.8, 39.9, 40.2, 40.5, 47.9, 48.0, 68.0,
118.3.
A Rep r esen ta tive P r oced u r e for CAN Oxid a tion of
Olefin -Teth er ed N,N-Dia lk ylcyclop r op yla m in es. To a
solution of cyclopropylamine 7a (29 mg, 0.1 mmol) in 5:1
MeOH-CH2Cl2 (6 mL) were added CAN (0.27 g, 0.5 mmol)
and NaHCO3 (42 mg, 0.5 mmol). The resulting mixture was
stirred at room temperature for 24 h and concentrated in
vacuo. The residue was dissolved in CH2Cl2 (10 mL) and 1 N
NaOH (2 mL). After the organic solution layer was separated,
the aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography (hexane; 10:1 hexane-
EtOAc; 30:1 CH2Cl2-EtOH) to afford the bicyclic products 25
and 26, in addition to the ring-opened ketone 9a and the
unreacted starting material 7a .
Ack n ow led gm en t. This paper is dedicated to Pro-
fessor J ack E. Baldwin, F.R.S., on the occasion of his
60th birthday. We thank the National Institutes of
Health (GM35956) for generous financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra (24 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9817671